Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition

• Published in: Nature medicine Vol. 22; no. 3; pp. 262 - 269
• Main Authors: Hata, Aaron N, Niederst, Matthew J, Archibald, Hannah L, Gomez-Caraballo, Maria, Siddiqui, Faria M, Mulvey, Hillary E, Maruvka, Yosef E, Ji, Fei, Bhang, Hyo-eun C, Krishnamurthy Radhakrishna, Viveksagar, Siravegna, Giulia, Hu, Haichuan, Raoof, Sana, Lockerman, Elizabeth, Kalsy, Anuj, Lee, Dana, Keating, Celina L, Ruddy, David A, Damon, Leah J, Crystal, Adam S, Costa, Carlotta, Piotrowska, Zofia, Bardelli, Alberto, Iafrate, Anthony J, Sadreyev, Ruslan I, Stegmeier, Frank, Getz, Gad, Sequist, Lecia V, Faber, Anthony C, Engelman, Jeffrey A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2016; Nature Publishing Group
• Subjects: 13/106; 14/35; 45/23; 64/60; 692/699/67/1059/2326; 692/699/67/1059/602; 96/2; 96/95; Apoptosis - drug effects; Apoptosis - genetics; Biomedicine; Blotting, Western; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Development and progression; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug therapy; Epidermal growth factor; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Humans; In Vitro Techniques; Infectious Diseases; Inhibitor drugs; Inhibitors; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Metabolic Diseases; Molecular Medicine; Mutation; Neurons; Neurosciences; Protein Kinase Inhibitors - pharmacology; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Tumors; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.4040

Drug-tolerant but initially EGFR T790M -negative tumor cells that undergo genetic evolution to acquire resistance to EGFR inhibitors are more resistant than pre-existing EGFR T790M -positive clones to subsequent therapy. Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR T790M gatekeeper mutation can occur either by selection of pre-existing EGFR T790M -positive clones or via genetic evolution of initially EGFR T790M -negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR T790M ; treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor–resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.